Many human pathogens show extensive antigenic diversity. Immunity from infection with one antigenic variant is often partially protective against infection with another antigenic variant, resulting in competition between antigenically similar strains for susceptible hosts. Understanding the immunological mechanisms underlying this competition is an important step in predicting strain dynamics, including such questions as whether a new antigenic variant will drive residents extinct, and how vaccination against some strains will affect competing strains that aren't targeted. Classic models of strain competition predict negative frequency-dependent selection driven by long-lasting, strain-specific immunity. Though sometimes a useful approximation, these simple models shed little light on how other known mechanisms of immunity might explain subtle differences in patterns of antigenic diversity of related pathogens. The goal of this project is to test the general hypothesis that different kinds of immunity shape population-level patterns in pathogen diversity. The first aim is to assess the roles of innate and antibody-based immunity in generating the patterns of antigenic diversity in two common bacterial pathogens, Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus). The respective contributions of each kind of immunity will be evaluated by comparing the observed prevalence of major antigenic types with results from an individual-based model in which the strength, breadth, and duration of heterologous immunity are varied in accordance with each type of immunity. The second aim uses the same three factors to infer the contributions of innate, cellular, and humoral immunity to the dynamics of two viruses, influenza and parainfluenza. The three factors will be estimated directly by fitting models of ordinary differential equations to time series of cases of each major antigenic type (serotypes 1-3 of parainfluenza and type A (subtype H3N2), A (H1N1), and B of influenza). The third aim explores to what extent differences between individual hosts might influence the outcomes of strain competition. These differences might have a genetic origin, such as hosts'MHC type I and II alleles, or derive from hosts'specific infection histories;preliminary work suggests highly biased responses to particular epitopes promote coexistence of antigenic types. To measure the effects of heterogeneous responses, individual-based models will be used to compare equilibrium and nonequilibrium diversity levels under assumptions of heterogeneity and homogeneity. This three-year postdoctoral research training plan will improve the investigator's understanding of the immunology of infectious diseases, the ways in which different immune mechanisms can affect host-pathogen dynamics, and which modeling approaches are appropriate in different situations. Augmented by a diverse set of professional training opportunities, this experience will prepare the investigator for an independent research position. This knowledge will ultimately be useful to the investigator and other scientists seeking to develop predictive models of the dynamics of competing pathogen strains. PUBLIC HEALTH RELEVANCE: Many common pathogens of humans show extensive antigenic diversity. The purpose of the proposed research is to use computational and mathematical models to test how different kinds of immunity mediate this diversity. This information will be useful for developing effective intervention strategies.